The goal of this program is to contribute to the elucidation of the pathogenesis of breast cancer, the most common malignancy in women. Hereditary cases, which constitute about 10% of all breast carcinomas, are associated with gemfiine mutations of minor suppressor genes such as BRCA1, BRCA2, ATM, p53, or PTEN, while sporadic cases are associated with somatic alterations of proto-oncogenes (e.g., c-MYC, ErbB2/neu, and Kras2) and tumor suppressor genes (e.g., PTEN and P53). Current data suggest that these and other genetic lesions promote breast cancer by deregulating specific signaling pathways that normally control the growth, death, differentiation, and genomic stability of mammary epithelial cells. Therefore, to attain a deeper understanding of breast cancer pathogenesis, it will be necessary to identify the individual components of these pathways and their interactions, to elucidate the molecular functions of each component, and to ascertain which of these pathways serve as targets for genetic lesions that contribute to human breast eancer. To this end, the following, projects will be pursued: Project 1 (R. Dalla-Favera) will study the role of the c-Myc pathway in breast carcinogenesis by focusing on Myc-interacting proteins and on proteins whose expression is regulated by c-Myc (Myc targets). Project 2 (A. Efstratiadis) will use mouse models of mammary carcinogenesis to study the causal role of known genetic alterations (c-MYC, Kras2, and ErbB2), as well as to identify novel alterations involved in tumor progression. Project 3 (R. Parsons) will focus on the role of the PTEN tumor suppressor and the PI3-kinase pathway in human breast cancer. Project 4 (R. Baer) will investigate the biochemical mechanism by which the BRCA1/BARD1 heterodbner mediates tumor suppression. Project 5 (T. Ludwig) will explore how genetic lesions of BRCA1 and its associated proteins (BARD1 and BACHI) promote mammary tumorigenesis. Project 6 (W. Gu) will study the regulation of the p53 pathway by the newly identified IIAUPT deubiquitination enzyme and explore its role as a tumor suppressor in breast cancer. These projects will be performed by a team of investigators with complementary expertise in molecular biology, mouse genetics, biochemistry, cell biology and pathology and will be supported by an a Genomics Core, and a Pathology Core.